Dressedin his usual blue jeans and yellow polo shirt, four-year old Bobby is in his room playing with his toy ball. He sits alone, concentrating intently on the ball. Bobby enjoys playing with this ball. In fact, for a little over a year now, Bobby insists on playing with this ball every afternoon after his lunch. He will sit silently for a couple of hours just respinning and watching the ball. For a while now, his parents have become worried about the amount of time Bobby spends alone with his ball. His mother has tried to get Bobby to play with other people. Unfortunately, every attempt has been unsuccessful. Sometimes, when Bobby is playing he will ignore other people and events. Other times, another person in the room will cause Bobby to panic. He will scream and hit himself repeatedly until the person leaves the room. Bobby cannot accustom himself to changes or new things. In fact, he finds no interest in other people and can barely recognize his parents. His autistic condition forces him to become emotionally and intellectually detached from the world in which he lives in.
Bobby is a fictional character, but his situation is typical of an autistic person. Autistic patients are characterized by their difficulty in interacting with others, their inability to speak and communicate, and their compulsions toward certain repetitive behaviors (DSM-IV). Their inclination towards repetition is the reason why many autistic individuals carry out strict routines and why they prefer to wear the same clothes every day. They are unable to divide their attention and thus are seen to be highly inattentive to their surroundings or too concentrated on one object. Their problems with attentiveness coupled with their inability and disinterest to communicate with others also explains their solitary behavior. Furthermore, patients with autism have self-injurious behavior, poor eye contact and sleep disorders (WWW I). Many autistic people are memory impaired and may be mentally retarded. These individuals are thus thought to lack a "theory of mind," a condition involving the solitary nature of the autistic person as a result of their inability to perceive, anticipate and communicate thoughts and actions of themselves and others. Autism is quite rare, affecting about 3-5 out of every 10,000 school-aged children (WWW 1). The signs of autism are evident by the time a child is two or three years old. However, subtle autistic symptoms present themselves in early infancy. Some signs might include: the infant becoming limp or stiff when picked up, lack of eye contact and the dislike of touch. The disorder affects mostly males (75%) and is shown to be genetically linked (WWW 2). Though there is no cure, scientists and psychologists have concluded that autism has a neurobiological basis and that pharmacological agents and psychotherapy can alleviate its symptoms.
Autism has been found to be associated with increased brain volume and problems in several regions of the brain. The affected brain regions include the cerebellum, medial temporal lobe, frontal lobe (prefrontal cortex) and corpus callosum. The cerebellum coordinates functions that influence attention, balance and proprioception. Hashimoto et al. (1995) found that in autistic patients, the cerebellum was reduced in size compared to normal individuals. This decreased size was found to be associated with hypoplasia and early developmental injuries as opposed to degeneration of the brain. Some researchers have also observed smaller vermal lobules VI-VII in autistic people (Courchesne et al. 1988). This condition is present in many individuals who suffer from other neurobiological disorders (Schafer et al. 1996). Thus, autistic characteristics such as inattentiveness and awkward body movements may be attributed to the reduced size of the cerebellum.
Abnormalities in the medial temporal lobe, including the amygdala, hippocampus and entorhinal cortex, contribute to impairments in face and emotion recognition, social stimuli, shared attention, symbolic play (make-believe that an object is something else), and motor imitation (Dawson et al. 1998). Damage to the amygdala is also associated with poor gaze directionality, the perception of body movements, and the inability to recall event sequences in autistic patients (Brothers et al. 1990; McDonough et al. 1994). The hippocampus region of the brain is a large contributor to memory. Thus abnormalities in this region also contributes to the underdeveloped recollective skills of autistic individuals. In addition, Bauman and Kemper (1994) noticed that neuronal cells were smaller in size and more densely packed in the amygdala, hippocampus, and nearby limbic regions in autistic brains. Thus, damage to these regions in the limbic region is thought to be the reason why persons with autism become detached from the world and avoid human contact. Lesions in the medial temporal lobe make it difficult for these individuals to "perceive the world the way we do" (WWW 1).
Abnormal structure in the frontal lobe is another characteristic of autistic persons (Piven et al. 1995; Damasio et al. 1980; Zilbovicius et al. 1995). The dorsolateral prefrontal cortex regulates working memory and response inhibition. Delayed response hinges on the ability to identify repeated actions in sequences after a short delay (5 sec.) of time. Defects to portions of the frontal lobe (prefrontal cortex) correlate to an autistic person's inability to recognize these sequences.
Lastly, abnormalities in the corpus callosum also contribute to autistic behavior. The corpus callosum is the main axonal pathway in the human brain and plays a role in the transfer of information between the brain hemispheres. Research has shown that this portion of the brain is significantly reduced in size in autistic individuals (Piven et al. 1997).
Patients with autism are also noted to have increased brain volume, especially in the mid-saggital and the posterior regions of the brain, including the parietal, temporal and occipital lobes (Piven et al. 1992, 1995). It has been observed that 250f autistic persons have a brain circumference greater than 970f the normal population (Bailey et al. 1995). This increase in brain volume is a result of a larger brain size and greater lateral ventricular and tissue mass (Piven et al. 1995). Global brain metabolism may be a cause of increased volume. The brain, namely the cerebrum, in autistic persons utilizes higher levels of glucose (Rumsey et al. 1985). However, in a small study, Buchsbaum et al. (1992) reported an opposing finding. He found that there was decreased metabolic activity in the subcortical areas. Unfortunately, the former finding has not been confirmed because this finding was only made in a small study of six subjects. Thus, due to lack of understanding of the relationship between autism and inter-regional brain volumes, a conclusion has not yet been made from these observations.
Aside from abnormalities and differences in the sizes of various regions of the brain and increased brain volume, neurochemical pathways also promote autistic characteristics. In fact, autism may result from the hyperfunction of the endogenous opioid system. Many autistic characteristics are similar to symptoms in humans and animals that have undergone opiate administration. These behaviors include insensitivity to pain, reduced crying, lack of socialization, repetitive mannerisms, convulsive activity and shifts between hyper and hypo-activity. The role of opioid receptors was hypothesized because of the insensitivity of autistic individuals to self-injurious activities (e.g. repeated hitting on the head). It is possible that through these seemingly painful activities, opioid levels increase in the body of an autistic person. Thus, increased opioid levels in the brain induce a euphoric sensation and result in a numbing pain sensation (Gillberg 1995). Furthermore, it is suspected that genetics factor into the increased endogenous opioid levels. However, it is unknown whether or not this results because of problems with opioid breakdown or faulty feedback mechanisms. Hyperfunctioning of the endogenous opioid system may also be influenced by the autistic individual's insufficient development. As a result of developmental retardation, the beta-endorphin levels in autistic individuals do not diminish, as they do in normal individuals, with age. The high levels of beta-endorphins allow the autistic person to receive excess stimulation from the opioid reward pathway. Interestingly, researchers suggest that the ability to create an internal excitement or high might be the cause of anti-social behavior in autistic people (Panksepp 1979). Thus, perhaps autistic individuals do not socialize because they have a condition that allows that to experience pleasurable sensations within themselves.
The overstimulation of the endogenous opioid system results in increased levels of serotonin in autistic individuals. Serotonin is associated with appetite, mood, sleep, anxiety, blood flow and aggressive behavior. Thus, in autistic persons, serotonin might contribute to reduced nutrient absorption, inability to sleep and self-injurious behavior. The reasons for high serotonin levels are investigated in several studies. Recent research also shows that the greater levels of serotonin are due to ineffective serotonin brain receptors or inadequate serotonin breakdown (Cook et al. 1997) This study also showed that mutated serotonin transporters may be a factor.
At this point, it should be noted that a differentiation between blood and brain serotonin has to be made. Unfortunately, only one study has results that compare the levels of blood versus brain serotonin. Interestingly, this study by Coleman et al (1977) showed that high levels of serotonin in the blood correlated with low serotonin levels in the brain, and vice versa. In addition, there has been a study that shows autism may result from antibodies in the cerebral spinal fluid and circulating blood that attempt to inhibit human brain serotonin receptors (Todd and Ciaranello 1985). Thus, as one considers serotonin related treatments, as later discussed, possible drug effects on the brain must be distinguished.
Other neurotransmitters that play a role in the opioid pathway include melatonin. and mono-amines. Increased levels of melatonin in the brain and blood induce high levels of serotonin. Melatonin is secreted by the pineal gland and plays a role in circadian rhythms and the immune system. A high level of melatonin in autistic individuals thus contributes to their hyperactivity and inability to sleep. Furthermore, heightened activity in the dopamine systems and hypoactivity of norepinephrine has been observed in autistic persons (Gillberg and Hamilton-Hellberg 1983; Gillberg and Svennerholm 1987). These increased amounts are present in the patient's blood and excretions. Unfortunately, these observations have not been followed with any concrete findings.
Nevertheless, scientists have found through increased genetic research that neurotransmitter abnormalities and characteristic autistic behavior are inherited. The chance of a second child developing autism is 6-8% though the observed rate is 30f autistic families. Though these values might appear small, this value is actually 100-200 times greater than the expected chance in the total human population (3-5 per 10,000) (Folstein et al. 1998). The genetics relating to autism cannot be explained in a Mendelian fashion because there are no dominant or recessive components that factor into the autistic phenotype. Instead, autism is the product of several gene mutations operating in concert. Autistic characteristics have been linked to almost every gene, except for Chromosomes 14 and 20. The most common gene mutations are on Chromosome 15 and the sex chromosomes.
Many persons with tri- and tetrasomy on Chromosome 15 exhibit autistic behavior and are diagnosed to be autistic. Chromosome 15 is also connected to Angelman syndrome, a disorder related to autism. The autistic behaviors associated with Chromosome 15 mutations are minor motor epilepsy, occasional spinal abnormalities and minor facial malformations, mental retardation. These phenotypes are present as a result of one of these mutations: inverted duplication of Chromosome 15p13, 15pter-q13, 15p1312, a duplication or microdeletion at Chromosome 15q11-13 (Gillberg 1998). Further findings show that the inverted duplication on 15p13q12 is maternally derived (Martinsson et al. 1996).
Chromosomal abnormalities relating to autism are also present on the X and Y chromosomes. The X chromosome has been linked to the Fragile X syndrome, another disorder linked with autism. This mutation is present on the Chromosome Xq27.3 (Feinstein & Reiss 1998). Further aberrations on the X-chromosome include a Xp22, a site associated with Rett syndrome (an autistic-linked disorder) and autism. As mentioned earlier, autism arises from the joint-action of several chromosomal mutations. An example includes a translocation of Xp22.13 with Chromosome 8q22.1 (Bolton et al. 1995). There are also a few papers about the relation of autism with Klinefelter (XXY), XXX and Turner (XO) syndromes. There have not been many findings regarding these cases. However, some correlation has been found between the X chromosome and mental retardation in some autistic individuals.
Chromosome Y variations have been associated with autism, Asperger syndrome (a autistic-linked disorder) and atypical autism. Autistic related abnormalities on the Y chromosome include long Y chromosome variants and translocations on Chromosome Yq12 and Chromosome 5p15.3, and aberrations such as XYY, 46XY and 46X (Gilberg 1998). Furthermore, XYY has been found to correlate with atypical autism/childhood psychosis. Some findings have also mutations on the Y chromosome resulting in XYY are linked with mosaicism (condition in which an organism is made up of genetically different tissues) in autistic individuals (Gillberg & Wahlstrom 1985; Gillberg 1995). Researchers have been able to find many autistic subjects who show aberrations in Chromosome 15 and the sex chromosomes. Less extensive studies have also linked: seizures with Chromosomes 1, 2, 6, and 17; moderate to severe mental retardation with Chromosomes 1, 4, 5, 7, 9, 16, 17, 18 and 22; autistic mannerisms/behavior with Chromosomes 1, 5, 8 and 21; minor physical abnormal characteristics with Chromosomes 1, 3, 6, 7, 13, 16, and 17 in autistic persons (Gillberg 1998). Furthermore, it should be noted that activity in the opioid and dopaminergic pathways is partially determined by genetic variables. In short, genetics play a large role in determining the levels of nervous activity, behavior, physiology and mental retardation in autistic individuals.
Understanding the neurobiological, neurochemical and genetic nature of autism allows for better specificity of treatment. Through targeting these neurological and inherited abnormalities, pharmacological and behavioral treatments for autistic persons. Many antipsychotic and antidepressent agents such as haloperidol, clomipramine, fluvoxamine and risperidone are used for lessening the symptoms of autism. The first generation of antipsychotic drugs used as medication for autistic persons included a phenylpiperidine analog, haloperidol. Because haloperidol is also used for the treatment of schizophrenia and obsessive-compulsive disorder, a correlation between autism and obsessive behavior is evident. Haloperidol is dopamine inhibitor. It has been found to be effective in reducing repetitive behaviors, hyperactivity, anxiety and irritability in autistic patients. Unfortunately, autistic children (40/118; 33.9%) developed drug-related dyskinesias as result of taking this drug over a long-term period (Campbell et al. 1997).
Due to the highly unwanted effects of haloperidol, a newer antipsychotic, risperidone has been used to reduce autistic symptoms. Risperidone is a serotonin (2A)-dopamine D2 antagonist. It has shown to reduce aggression, repetitive behavior, nervousness, irritability and depression and autistic behavior (McDougle et al. 1998). Additionally, it is effective in low doses. Unfortunately, the drug does not seem to promote a change or improvement in language skills and social behavior. The side effects for risperidone have been minimal, with no sign of seizure or abnormal cardiac problems. The usual negative effects, as reported by a large number of patients, has been brief, mild sedation and weight gain (in children and adolescents). However there have been rare reports of one individual who developed an abnormal gait and another who became more agitated in response to risperidone (McDougle et al., 1998). Unfortunately in recent reports, children who are being treated with risperidone also developed tardive dyskinesia (Feeney & Klykylo 1996). However, more controlled research is necessary to determine whether risperidone can be taken by adults.
Thus antidepressants like clomipramine and floxetine have been used to reduce autistic symptoms. These drugs are more effective than the mentioned antipsychotic agents because they have been proven to improve social behavior amongst autistic persons (McDougle et al. 1998) Both compounds have been used successfully in reducing obsessive repetitive behaviors and aggressiveness. Yet, floxetine is preferred over clomipramine because of its specific inhibitory actions and milder side effects. Clomipramine is a serotonin and norepinephrine pump inhibitor that has high sedating effects and moderate anti-muscarinic effects (e.g. dry mouth, constipation). Floxetine works more efficiently and specifically as a selective serotonin reuptake inhibitors (SSRIs). Floxetine is preferred because it is effective in lower doses. Also, unlike clomipramine, it is non-sedating and has no anti-muscarinic effects. However, SSRIs can have side effects such as nausea and decreased sexual drive and function.
Aside from formulating pharmacological agents, scientists are also looking toward new approaches in behavioral training to treat autistic symptoms. Behavioral educators attend to problems inherent in autistic behavior through exercises that teach correct manners and thinking. The lessons involve operant and classical conditioning (WWW 2). The latter deals with changes in stimuli and situations to enhance learning of a specific behavior. The former method acknowledges right or wrong responses with rewards and punishments. Behavior treatments attempt to make the autistic person's brain more accustomed to the environment. Thus, this type of education is appropriate if proper stimuli, whether it is result of the treatment or the environment, helps the autistic patient learn.
Another treatment that stimulates behavioral changes requires the use of wearing ambient transitional prism lenses. Kaplan et al. (1998) has found that wearing ambient lenses and training in the coordination of muscles and eyes can improve visual-motor coordination, movement, orientation, attention and posture. These lenses are so practical because many autistic persons suffer from visual distortion. Autistic individuals may have strabismus. Thus, they rely on their peripheral vision and have a reduced field of vision. The lenses shift the degree of sight to encompass a larger visual field. The autistic individual is now able to identify people and objects with more precision. Also, the ambient lenses allow the patient to realize his/her position with respect to the environment because of the gained ability to perceive depth in space. Thus, both behavioral therapies and drug treatments allow the autistic individual to adjust their response to the environment.
Though some drug preparations and behavioral therapies are available, scientists are still searching for a treatment that all autistic individuals can respond (positively) to. Until recently, this task of finding treatment was extremely difficult because the definition of autism as the nature of the disorder was not totally understood. However, with the help of genetic engineering, current research has uncovered the complex nature of autism. Multiple factors including neurobiological, neurochemical and genetic abnormalities were found to play a role in this disorder. With this knowledge at hand, scientists hope to develop a treatment plan that can focus in on treating the autistic mind. As Yirmiya writes, " the construction of the mind is universal" (Yirmiya et al. 1998). Thus, we must attempt to integrate the restoration of proper brain function with appropriate social development in the treatment of autistic persons.
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WWW 1. http://www.autism-zone.com/autism/review.htm
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